Abstract

Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies.

A generic metabolomics workflow. Samples are harvested and minimally processed before NMR or MS analysis. Features are selected from the data set, aligned, integrated and scaled before statistical analysis and compound identification. Identified compounds may then be mapped to biological pathways for interpretation. Each step may vary depending on the experimental design and analytical technique.

Mechanisms of glucose stimulated insulin secretion (GSIS) and suggested stimulus/secretion coupling factors. The canonical model of GSIS holds that an increase in β-cell glycolytic and mitochondrial metabolism of glucose lead to increases in cytosolic ATP:ADP ratio, resulting in closure of ATP-sensitive K+ (KATP) channels, plasma membrane depolarization, activation of voltage-dependent Ca2+ channels and Ca2+-mediated activation of insulin granule exocytosis. β-cells have high capacity for anaplerotic influx of glucose-derived pyruvate into the TCA cycle via pyruvate carboxylase (PC), which in turn is paired with efflux of citrate and isocitrate via the citrate-isocitrate carrier (CIC), and cytosolic isocitrate dehydrogenase (ICDc)-mediated conversion of isocitrate into α-ketoglutarate under generation of NADPH, a suggested coupling factor for GSIS. NADPH is also generated to lesser degree in the pentose phosphate pathway (PPP), a revived pathway of interest for regulation of GSIS. Other suggested metabolic coupling factors include glutamate, GTP, protein prenylation and two new candidates, ZMP and GDP-mannose identified from metabolomics studies. Fatty acids potentiate GSIS via mechanisms that involve activation of the surface receptor FFAR/GPR40 as well as intracellular fatty acid metabolism, and fatty acid-mediated coupling factor candidates include glycerolipids such as monoacylglycerol. GSIS is also amplified by incretins secreted from the small intestine in response to a meal. A recent metabolomics study has identified a novel pathway involving cytosolic glutamate derived from glucose to a signal for incretin-induced insulin secretion (see text for details). G3P: glycerol-3-phosphate; G6P: glucose -6-phosphate; GRX: glutaredoxin; GSH: reduced glutathione; R5P: ribose-5-phosphate; M6P: mannose-6-phosphate.